Substance dependence, also known as drug dependence, is an adaptive state that develops from repeated drug administration, and which results in withdrawal upon cessation of drug use.[1][2] A drug addiction, a distinct concept from substance dependence, is defined as compulsive, out-of-control drug use, despite negative consequences.[1][2] An addictive drug is a drug which is both rewarding and reinforcing.[1]ΔFosB, a gene transcription factor, is now known to be a critical component and common factor in the development of virtually all forms of behavioral addiction and drug addictions,[3][4][5] but not dependence.

Within the framework of the 4th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), substance dependence is redefined as a drug addiction, and can be diagnosed without the occurrence of a withdrawal syndrome.[6] It is now described accordingly: "When an individual persists in use of alcohol or other drugs despite problems related to use of the substance, substance dependence may be diagnosed. Compulsive and repetitive use may result in tolerance to the effect of the drug and withdrawal symptoms when use is reduced or stopped. This, along with Substance Abuse are considered Substance Use Disorders."[7]

Withdrawal is the body's reaction to abstaining from a substance upon which a person has developed a dependence syndrome. When dependence has developed, cessation of substance use produces an unpleasant state, which promotes continued drug use through negative reinforcement; i.e., the drug is used to escape or avoid re-entering the associated withdrawal state. The withdrawal state may include physical-somatic symptoms (physical dependence), emotional-motivational symptoms (psychological dependence), or both. Chemical and hormonal imbalances may arise if the substance is not introduced. Psychological stress may also result if the substance is not re-introduced.[citation needed]
Infants also suffer from substance withdrawal, known as Neonnatal Abstinence Syndrome (NAS) which has severe and life-threatening effects on growing fetus. Addiction to drugs and alcohol in expecting mothers does not only cause NAS but also an array of other issues which can continually affect the infant throughout his/her lifetime. The type of drug which was abused during the months of pregnancy has many different effects on the child which can affect the infant in many ways throughout his/her life.[12]

The dependence potential of a drug varies from substance to substance, and from individual to individual. Dose, frequency, pharmacokinetics of a particular substance, route of administration, and time are critical factors for developing a drug dependence.

An article in The Lancet compared the harm and dependence liability of 20 drugs, using a scale from zero to three for physical dependence, psychological dependence, and pleasure to create a mean score for dependence. Selected results can be seen in the chart below.[13]

In addition to CREB, it is hypothesized that stress mechanisms play a role in dependence. Koob and Kreek have hypothesized that during drug use, CRF activates the hypothalamic–pituitary–adrenal axis (HPA axis) and other stress systems in the extended amygdala. This activation influences the dysregulated emotional state associated with psychological dependence. They found that as drug use escalates, so does the presence of CRF in human cerebrospinal fluid. In rat models, the separate use of CRF inhibitors and CRF receptor antagonists both decreased self-administration of the drug of study. Other studies in this review showed dysregulation of other neuropeptides that affect the HPA axis, including enkephalin which is an endogenous opioid peptide that regulates pain. It also appears that µ-opioid receptors, which enkephalin acts upon, is influential in the reward system and can regulate the expression of stress hormones.[17]

Increased expression of AMPA receptors in nucleus accumbens MSNs is a potential mechanism of aversion produced by drug withdrawal.[18]

This section needs expansion. You can help by adding to it.(March 2016)

Upregulation of the cAMPsignal transduction pathway in the locus coeruleus by CREB has been implicated as the mechanism responsible for certain aspects of opioid-induced physical dependence.[19] The temporal course of withdrawal correlates with LC firing, and administration of α2 agonists into the locus coeruleus leads to a decrease in LC firing and norepinephrine release during withdrawal. A possible mechanism involves upregulation of NMDA receptors, which is supported by the attenuation of withdraw by NMDA receptor antagonists.[20] Physical dependence on opioids has been observed to produce an elevation of extracellular glutamate, an increase in NMDA receptor subunits NR1 and NR2A, phosphorylated CaMKII, and c-fos. Expression of CaMKII and c-fos is attenuated by NMDA receptor antagonists, which is associated with blunted withdrawal in adult rats, but not neonatal rats[21] While acute administration of opioids decreases AMPA receptor expression and depresses both NMDA and non-NMDA excitatory postsynaptic potentials in the NAC, withdrawal involves a lowered threshold for LTP and an increase in spotaneous firing in the NAc.[22]

"Substance dependence", as defined in the DSM, can be diagnosed with physiological dependence, evidence of tolerance or withdrawal, or without physiological dependence.
DSM-5 substance dependencies include:

Addiction is a complex but treatable condition. It is characterized by compulsive drug craving, seeking, and use that persists even if the user is aware of severe adverse consequences. For some people, addiction becomes chronic, with periodic relapses even after long periods of abstinence. As a chronic, relapsing disease, addiction may require continued treatments to increase the intervals between relapses and diminish their intensity. While some with substance issues recover and lead fulfilling lives, others require ongoing additional support. The ultimate goal of addiction treatment is to enable an individual to manage their substance misuse; for some this may mean abstinence. Immediate goals are often to reduce substance abuse, improve the patient's ability to function, and minimize the medical and social complications of substance abuse and their addiction; this is called "harm reduction".

Treatments for addiction vary widely according to the types of drugs involved, amount of drugs used, duration of the drug addiction, medical complications and the social needs of the individual. Determining the best type of recovery program for an addicted person depends on a number of factors, including: personality, drugs of choice, concept of spirituality or religion, mental or physical illness, and local availability and affordability of programs.

Many different ideas circulate regarding what is considered a successful outcome in the recovery from addiction. Programs that emphasize controlled drinking exist for alcohol addiction. Opiate replacement therapy has been a medical standard of treatment for opioid addiction for many years.

Treatments and attitudes toward addiction vary widely among different countries. In the US and developing countries, the goal of commissioners of treatment for drug dependence is generally total abstinence from all drugs. Other countries, particularly in Europe, argue the aims of treatment for drug dependence are more complex, with treatment aims including reduction in use to the point that drug use no longer interferes with normal activities such as work and family commitments; shifting the addict away from more dangerous routes of drug administration such as injecting to safer routes such as oral administration; reduction in crime committed by drug addicts; and treatment of other comorbid conditions such as AIDS, hepatitis and mental health disorders. These kinds of outcomes can be achieved without eliminating drug use completely. Drug treatment programs in Europe often report more favorable outcomes than those in the US because the criteria for measuring success are functional rather than abstinence-based.[23][24][25] The supporters of programs with total abstinence from drugs as a goal believe that enabling further drug use means prolonged drug use and risks an increase in addiction and complications from addiction.[26]

Residential drug treatment can be broadly divided into two camps: 12-step programs and therapeutic communities. Twelve-step programs are a nonclinical support-group and faith-based approach to treating addiction. Therapy typically involves the use of cognitive-behavioral therapy, an approach that looks at the relationship between thoughts, feelings and behaviors, addressing the root cause of maladaptive behavior. Cognitive-behavioral therapy treats addiction as a behavior rather than a disease, and so is subsequently curable, or rather, unlearnable. Cognitive-behavioral therapy programs recognize that, for some individuals, controlled use is a more realistic possibility.[27]

One of many recovery methods are 12-step recovery programs, with prominent examples including Alcoholics Anonymous, Narcotics Anonymous, Drug Addicts Anonymous[28] and Pills Anonymous. They are commonly known and used for a variety of addictions for the individual addicted and the family of the individual. Substance-abuse rehabilitation (rehab) centers offer a residential treatment program for some of the more seriously addicted, in order to isolate the patient from drugs and interactions with other users and dealers. Outpatient clinics usually offer a combination of individual counseling and group counseling. Frequently, a physician or psychiatrist will prescribe medications in order to help patients cope with the side effects of their addiction. Medications can help immensely with anxiety and insomnia, can treat underlying mental disorders (cf. self-medication hypothesis, Khantzian 1997) such as depression, and can help reduce or eliminate withdrawal symptomology when withdrawing from physiologically addictive drugs. Some examples are using benzodiazepines for alcohol detoxification, which prevents delirium tremens and complications; using a slow taper of benzodiazepines or a taper of phenobarbital, sometimes including another antiepileptic agent such as gabapentin, pregabalin, or valproate, for withdrawal from barbiturates or benzodiazepines; using drugs such as baclofen to reduce cravings and propensity for relapse amongst addicts to any drug, especially effective in stimulant users, and alcoholics (in which it is nearly as effective as benzodiazepines in preventing complications); using clonidine, an alpha-agonist, and loperamide for opioid detoxification, for first-time users or those who wish to attempt an abstinence-based recovery (90% of opioid users relapse to active addiction within eight months or are multiple relapse patients); or replacing an opioid that is interfering with or destructive to a user's life, such as illicitly-obtained heroin, dilaudid, or oxycodone, with an opioid that can be administered legally, reduces or eliminates drug cravings, and does not produce a high, such as methadone or buprenorphine – opioid replacement therapy – which is the gold standard for treatment of opioid dependence in developed countries, reducing the risk and cost to both user and society more effectively than any other treatment modality (for opioid dependence), and shows the best short-term and long-term gains for the user, with the greatest longevity, least risk of fatality, greatest quality of life, and lowest risk of relapse and legal issues including arrest and incarceration.[citation needed]

In a survey of treatment providers from three separate institutions, the National Association of Alcoholism and Drug Abuse Counselors, Rational Recovery Systems and the Society of Psychologists in Addictive Behaviors, measuring the treatment provider's responses on the "Spiritual Belief Scale" (a scale measuring belief in the four spiritual characteristics of AA identified by Ernest Kurtz); the scores were found to explain 41% of the variance in the treatment provider's responses on the "Addiction Belief Scale" (a scale measuring adherence to the disease model or the free-will model of addiction).[29]

Behavioral programming is considered critical in helping those with addictions achieve abstinence. From the applied behavior analysis literature and the behavioral psychology literature, several evidence based intervention programs have emerged: (1) behavioral marital therapy; (2) community reinforcement approach; (3) cue exposure therapy; and (4) contingency management strategies.[30][31] In addition, the same author suggest that Social skills training adjunctive to inpatient treatment of alcohol dependence is probably efficacious. Community reinforcement has both efficacy and effectiveness data.[32] In addition, behavioral treatment such as community reinforcement and family training (CRAFT) have helped family members to get their loved ones into treatment.[33][34] Motivational Intervention has also shown to be an effective treatment for substance dependence.

Alternative therapies, such as acupuncture, are used by some practitioners to alleviate the symptoms of drug addiction. In 1997, the American Medical Association (AMA) adopted as policy the following statement after a report on a number of alternative therapies including acupuncture:

There is little evidence to confirm the safety or efficacy of most alternative therapies. Much of the information currently known about these therapies makes it clear that many have not been shown to be efficacious. Well-designed, stringently controlled research should be done to evaluate the efficacy of alternative therapies.[35]

However, a review of 48 clinical trials on alcohol, cocaine, nicotine, and opioid dependence showed that acupuncture has promising outcomes for craving and withdrawal, specifically through body acupuncture, electroacupuncture, and bilateral needling. However, the effect of acupuncture on withdrawal was transient and thus needed to be repeated several times a day.[36]

Another alternative therapy for substance dependence is yoga and mindfulness-based therapies. Those struggling with addiction often feel disconnected from their bodies and use substances to block out any painful thoughts and experiences. Thus, they may not be fully aware at the present moment. Mindfulness training can bring back awareness and allow individuals to more effectively manage those painful situations, rather than default to substance use as a coping mechanism. Mindfulness can be practiced in many forms, from becoming more engaged and alert on a daily basis to more formal meditation. Yoga is one form of "meditative movement" that can be effective in fostering emotion regulation and enable individuals to instill a greater sense of connection with their bodies. This can help overcome any negative feelings of isolation and shame associated with addiction, as well as improve self-regulation. [37]

Biofeedback programs are another alternative method that can connect individuals to a technological device and enable them to track their body's physiological changes, such as heart rate, skin conductance, and muscle tension. Neurofeedback is a branch of biofeedback technology that measures brain activity through EEG. By examining what factors may affect these parameters positively or negatively, individuals can train their mind and body to act in a certain way that will help enhance emotional, cognitive, physical and behavioral experiences. Particularly, they can learn to better cope with emotional stress and develop skills in self-regulation, all of which can be beneficial in managing addiction. [38]

Psychologists need to use many techniques and approaches to implement the right application to fix substance related disorders. Psychodynamic approach is one of the techniques that psychologist use to solve addiction problems. In psychodynamic therapy, psychologists need to understand the conflicts and the needs of the addicted person, and also need to locate the defects of their ego and defense mechanisms. Using this approach alone has proven to be ineffective in solving addiction problems. Psychology is not only defined by the conscious as is believed in structuralism ideology, it is also defined by cognition and behavior. Therefore, cognitive and behavioral techniques should be integrated with psychodynamic approaches to achieve effective treatment to substance related disorders[39](Cornish et al., 1995; Lightdale et al., 2011, 2008). Cognitive treatment requires psychologists to think deeply about what is happening in the brain of an addicted person. Cognitive psychologists should zoom in to neural functions of the brain and understand that drugs have been manipulating the dopamine reward center of the brain. From this particular state of thinking, cognitive psychologists need to find ways to change the thought process of the addicted person[39](de Wit and Phan, 2010).

There are two routes that should be applied to cognitively approaching a fix for substance abuse: track the thoughts that pulled them to addiction and track the thoughts that prevent them from relapsing. Psychologists should also add the principle of functionalism in the equation of treating a substance related disorder. Behavioral techniques have the largest wide share of application in treating substance related disorders. Behavioral psychologists would use the techniques of “aversion therapy,” based on the principles of Pavlov'sclassical conditioning. It is when pairing substance abuse with unpleasant stimulus or condition, for example, pairing pain, electrical shock, or nausea with alcohol consumption. The latter requires using some nausea-induced medications [39](Owen-Howard, 2010; Welsh & Liberto, 2001). Psychologists tend to use an integration of all these approaches to produce reliable and effective treatment. With advanced clinical use of medications, biological treatment has considered to be one of the efficient interventions that psychologists may use as a short cut treatment for addict persons. Biological interventions involved many approaches; one approach is to reduce regularly the dosages intake of the harmful substances.

The other approach is to use medicines that contain chemicals that interfere with the functions of the drugs in the brain. The third approach is when substituting addiction drugs with other addiction drugs. The next paragraph would explain how this approach is problematic and involve in the debate of ethical concerns. Those three conditions of biological interventions have aimed on the process of detoxification within the substance abuse individuals, especially the ones whose drugs become the center of their life. Psychologists need to think of the consequences when understanding how the process of detoxification is a difficult stage and might throw individuals with addiction problems into unpleasant conditions and painful experience. Moreover, Psychologist needs to realize that by using biological interventions they are purposely and intentionally throwing drug abusive people into unwanted withdrawal symptoms. This might inflict pain and dangerous consequences on the addict persons. Therefore, biological intervention should be combined with Humanistic approaches and other therapeutic techniques. Self- Help therapies is a group therapy technique which include anonymity, teamwork and sharing concerns of daily life among people who suffer from addiction issues. However, these programs proved to be only effective and influential on persons who did not reach the level of serious dependency on drugs or alcohol. Self-help therapy proved to be effective on young people who have self-conscious about their problems.[39]

The phenomenon of drug addiction has occurred to some degree throughout recorded history (see "Opium").[40] Modern agricultural practices, improvements in access to drugs, advancements in biochemistry, and dramatic increases in the recommendation of drug usage by clinical practitioners have exacerbated the problem significantly in the 20th century. Improved means of active biological agent manufacture and the introduction of synthetic compounds, such as methamphetamine, are also factors contributing to drug addiction.[41][42]

For the entirety of US history, drugs have been used by some members of the population. In the country's early years, most drug use by the settlers was of alcohol or tobacco.[43]

The nineteenth century saw opium usage in the US become much more common and popular. Morphine was isolated in the early nineteenth century, and came to be prescribed commonly by doctors, both as a painkiller and as an intended cure for opium addiction. At the time, the prevailing medical opinion was that the addiction process occurred in the stomach, and thus it was hypothesized that patients would not become addicted to morphine if it was injected into them via a hypodermic needle, and it was further hypothesized that this might potentially be able to cure opium addiction. However, many people did become addicted to morphine. In particular, addiction to opium became widespread among soldiers fighting in the Civil War, who very often required painkillers and thus were very often prescribed morphine. Women were also very frequently prescribed opiates, and opiates were advertised as being able to relieve "female troubles".[43]

Many soldiers in the Vietnam War were introduced to heroin and many developed a dependency to the substance which survived even when they returned to the US. Technological advances in travel meant that this increased demand for heroin in the US could now be met. Furthermore, as technology advanced, more drugs were synthesized and discovered, opening up new avenues to substance dependency.[43]

Internationally, the U.S. and Eastern Europe are the countries with the highest substance abuse disorder occurrence (5-6%). Africa, Asia, and the Middle East were countries with the lowest worldwide occurrence (1-2%). Across the globe, those that tended to have a higher prevalence of substance dependence were in their twenties, unemployed, and men.[44] The National Survey on Drug Use and Health (NSDUH) reports on substance dependence/abuse rates in various population demographics across the U.S. When surveying populations based on race and ethnicity in those ages 12 and older, it was observed that American Indian/Alaskan Natives were among the highest rates and Asians were among the lowest rates in comparison to other racial/ethnic groups.[45]

When surveying populations based on gender in those ages 12 and older, it was observed that males had a higher substance dependence rate than females. However, the difference in the rates aren't apparent until after age 17.[45] The Drug and Alcohol Dependence reports that older adults abuse drugs and alcohol at a rate of 15-20%. It's estimated that 52 million Americans beyond 12 years old have abused a substance.[46]

Substance Use in Gender Populations w/ Respect to Age

Age

Male

Female

12 and older

10.8%

5.8%

12-17

5.3%

5.2%

18 or older

11.4%

5.8%

Alcohol dependence or abuse rates were shown to have no correspondence with any person's education level when populations were surveyed in varying degrees of education from ages 26 and older. However, when it came to illicit drug use there was a correlation, in which those that graduated from college had the lowest rates. Furthermore, dependence rates were greater in unemployed populations ages 18 and older and in metropolitan-residing populations ages 12 and older.[45]

The National Opinion Research Center at the University of Chicago reported an analysis on disparities within admissions for substance abuse treatment in the Appalachian region, which comprises 13 states and 410 counties in the Eastern part of the U.S. While their findings for most demographic categories were similar to the national findings by NSDUH, they had different results for racial/ethnic groups which varied by sub-regions. Overall, Whites were the demographic with the largest admission rate (83%), while Alaskan Native, American Indian, Pacific Islander, and Asian populations had the lowest admissions (1.8%).[47]

Depending on the jurisdiction, addictive drugs may be legal, legal only as part of a government sponsored study, illegal to use for any purpose, illegal to sell, or even illegal to merely possess.

Most countries have legislation which brings various drugs and drug-like substances under the control of licensing systems. Typically this legislation covers any or all of the opiates, amphetamines, cannabinoids, cocaine, barbiturates, benzodiazepines, anesthetics, hallucinogenics, derivatives and a variety of more modern synthetic drugs. Unlicensed production, supply or possession is a criminal offence.

Usually, however, drug classification under such legislation is not related simply to addictiveness. The substances covered often have very different addictive properties. Some are highly prone to cause physical dependency, while others rarely cause any form of compulsive need whatsoever. Also, under legislation specifically about drugs, alcohol and nicotine are not usually included.

Although the legislation may be justifiable on moral or public health grounds, it can make addiction or dependency a much more serious issue for the individual: reliable supplies of a drug become difficult to secure, and the individual becomes vulnerable to both criminal abuse and legal punishment.

It is unclear whether laws against illegal drug use do anything to stem usage and dependency. In jurisdictions where addictive drugs are illegal, they are generally supplied by drug dealers, who are often involved with organized crime. Even though the cost of producing most illegal addictive substances is very low, their illegality combined with the addict's need permits the seller to command a premium price, often hundreds of times the production cost. As a result, addicts sometimes turn to crime to support their habit.

In the United States, drug policy is primarily controlled by the federal government. The Department of Justice's Drug Enforcement Administration (DEA) enforces controlled substances laws and regulations. The Department of Health and Human Services' Food and Drug Administration (FDA) serve to protect and promote public health by controlling the manufacturing, marketing, and distribution of products, like medications.

The United States' approach to substance abuse has shifted over the last decade, and is continuing to change. The federal government was minimally involved in the 19th century. The federal government transitioned from using taxation of drugs in the early 20th century to criminalizing drug abuse with legislations and agencies like the Federal Bureau of Narcotics (FBN) mid-20th century in response to the nation's growing substance abuse issue.[48] These strict punishments for drug offenses shined light on the fact that drug abuse was a multi-faceted problem. The President's Advisory Commission on Narcotics and Drug Abuse of 1963 addressed the need for a medical solution to drug abuse. However, drug abuse continued to be enforced by the federal government through agencies such as the DEA and further legislations such as The Controlled Substances Act (CSA), the Comprehensive Crime Control Act of 1984, and Anti-Drug Abuse Acts.

In the past decade, there have been growing efforts through state and local legislations to shift from criminalizing drug abuse to treating it as a health condition requiring medical intervention. 9 states have legislations for safe syringe use like exchange programs or purchasing at pharmacy. In addition, AB-186 Controlled substances: overdose prevention program was introduced to operate safe injection sites in the City and County of San Francisco. The bill was vetoed on September 30, 2018 by California Governor Jerry Brown.[49] The legality of these sites are still in discussion, so there are no such sites in the United States yet. However, there is growing international evidence for successful safe injection facilities.

^ abcMalenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and Addictive Disorders". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 364–368. ISBN9780071481274. The defining feature of addiction is compulsive, out-of-control drug use, despite negative consequences. ...Addictive drugs are both rewarding and reinforcing. ... Familiar pharmacologic terms such as tolerance, dependence, and sensitization are useful in describing some of the time-dependent processes that underlie addiction. ... Dependence is defined as an adaptive state that develops in response to repeated drug administration, and is unmasked during withdrawal, which occurs when drug taking stops. Dependence from long-term drug use may have both a somatic component, manifested by physical symptoms, and an emotional–motivation component, manifested by dysphoria. While physical dependence and withdrawal occur with some drugs of abuse (opiates, ethanol), these phenomena are not useful in the diagnosis of addiction because they do not occur with other drugs of abuse (cocaine, amphetamine) and can occur with many drugs that are not abused (propranolol, clonidine).

The official diagnosis of drug addiction by the Diagnostic and Statistic Manual of Mental Disorders (2000), which makes distinctions between drug use, abuse, and substance dependence, is flawed. First, diagnosis of drug use versus abuse can be arbitrary and reflect cultural norms, not medical phenomena. Second, the term substance dependence implies that dependence is the primary pharmacologic phenomenon underlying addiction, which is likely not true, as tolerance, sensitization, and learning and memory also play central roles. It is ironic and unfortunate that the Manual avoids use of the term addiction, which provides the best description of the clinical syndrome.

^ ab"Substance use disorder". Pubmed Health. National Institutes of Health. Archived from the original on 31 March 2014. Retrieved 12 September 2014. Drug dependence means that a person needs a drug to function normally. Abruptly stopping the drug leads to withdrawal symptoms. Drug addiction is the compulsive use of a substance, despite its negative or dangerous effects

^Robison AJ, Nestler EJ (October 2011). "Transcriptional and epigenetic mechanisms of addiction". Nature Reviews. Neuroscience. 12 (11): 623–37. doi:10.1038/nrn3111. PMC3272277. PMID21989194. ΔFosB has been linked directly to several addiction-related behaviors ... Importantly, genetic or viral overexpression of ΔJunD, a dominant negative mutant of JunD which antagonizes ΔFosB- and other AP-1-mediated transcriptional activity, in the NAc or OFC blocks these key effects of drug exposure14,22–24. This indicates that ΔFosB is both necessary and sufficient for many of the changes wrought in the brain by chronic drug exposure. ΔFosB is also induced in D1-type NAc MSNs by chronic consumption of several natural rewards, including sucrose, high fat food, sex, wheel running, where it promotes that consumption14,26–30. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states.

^Blum K, Werner T, Carnes S, Carnes P, Bowirrat A, Giordano J, Oscar-Berman M, Gold M (2012). "Sex, drugs, and rock 'n' roll: hypothesizing common mesolimbic activation as a function of reward gene polymorphisms". Journal of Psychoactive Drugs. 44 (1): 38–55. doi:10.1080/02791072.2012.662112. PMC4040958. PMID22641964. It has been found that deltaFosB gene in the NAc is critical for reinforcing effects of sexual reward. Pitchers and colleagues (2010) reported that sexual experience was shown to cause DeltaFosB accumulation in several limbic brain regions including the NAc, medial pre-frontal cortex, VTA, caudate, and putamen, but not the medial preoptic nucleus. Next, the induction of c-Fos, a downstream (repressed) target of DeltaFosB, was measured in sexually experienced and naive animals. The number of mating-induced c-Fos-IR cells was significantly decreased in sexually experienced animals compared to sexually naive controls. Finally, DeltaFosB levels and its activity in the NAc were manipulated using viral-mediated gene transfer to study its potential role in mediating sexual experience and experience-induced facilitation of sexual performance. Animals with DeltaFosB overexpression displayed enhanced facilitation of sexual performance with sexual experience relative to controls. In contrast, the expression of DeltaJunD, a dominant-negative binding partner of DeltaFosB, attenuated sexual experience-induced facilitation of sexual performance, and stunted long-term maintenance of facilitation compared to DeltaFosB overexpressing group. Together, these findings support a critical role for DeltaFosB expression in the NAc in the reinforcing effects of sexual behavior and sexual experience-induced facilitation of sexual performance. ... both drug addiction and sexual addiction represent pathological forms of neuroplasticity along with the emergence of aberrant behaviors involving a cascade of neurochemical changes mainly in the brain's rewarding circuitry.

^Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues Clin. Neurosci. 15 (4): 431–443. PMC3898681. PMID24459410. Despite the importance of numerous psychosocial factors, at its core, drug addiction involves a biological process: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. ... A large body of literature has demonstrated that such ΔFosB induction in D1-type [nucleus accumbens] neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement ... Another ΔFosB target is cFos: as ΔFosB accumulates with repeated drug exposure it represses c-Fos and contributes to the molecular switch whereby ΔFosB is selectively induced in the chronic drug-treated state.41. ... Moreover, there is increasing evidence that, despite a range of genetic risks for addiction across the population, exposure to sufficiently high doses of a drug for long periods of time can transform someone who has relatively lower genetic loading into an addict.

^"Glossary of Terms". Mount Sinai School of Medicine. Department of Neuroscience. Retrieved 9 February 2015.

^Volkow ND, Koob GF, McLellan AT (January 2016). "Neurobiologic Advances from the Brain Disease Model of Addiction". N. Engl. J. Med. 374 (4): 363–371. doi:10.1056/NEJMra1511480. PMID26816013. Substance-use disorder: A diagnostic term in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) referring to recurrent use of alcohol or other drugs that causes clinically and functionally significant impairment, such as health problems, disability, and failure to meet major responsibilities at work, school, or home. Depending on the level of severity, this disorder is classified as mild, moderate, or severe.Addiction: A term used to indicate the most severe, chronic stage of substance-use disorder, in which there is a substantial loss of self-control, as indicated by compulsive drug taking despite the desire to stop taking the drug. In the DSM-5, the term addiction is synonymous with the classification of severe substance-use disorder.

^Nestler EJ (August 2016). "Reflections on: "A general role for adaptations in G-Proteins and the cyclic AMP system in mediating the chronic actions of morphine and cocaine on neuronal function"". Brain Research. 1645: 71–4. doi:10.1016/j.brainres.2015.12.039. PMC4927417. PMID26740398. These findings led us to hypothesize that a concerted upregulation of the cAMP pathway is a general mechanism of opiate tolerance and dependence. ... We thus extended our hypothesis to suggest that, particularly within brain reward regions such as NAc, cAMP pathway upregulation represents a common mechanism of reward tolerance and dependence shared by several classes of drugs of abuse. Research since that time, by many laboratories, has provided substantial support for these hypotheses. Specifically, opiates in several CNS regions including NAc, and cocaine more selectively in NAc induce expression of certain adenylyl cyclase isoforms and PKA subunits via the transcription factor, CREB, and these transcriptional adaptations serve a homeostatic function to oppose drug action. In certain brain regions, such as locus coeruleus, these adaptations mediate aspects of physical opiate dependence and withdrawal, whereas in NAc they mediate reward tolerance and dependence that drives increased drug self-administration.